Lb. Zhou et al., TEPOXALIN BLOCKS NEUTROPHIL MIGRATION INTO CUTANEOUS INFLAMMATORY SITES BY INHIBITING MAC-1 AND E-SELECTIN EXPRESSION, European Journal of Immunology, 26(1), 1996, pp. 120-129
Inflammation is characterized by the migration of polymorphonuclear le
ukocytes from the vasculature into the tissue causing profound injury.
Adhesion and migration of neutrophils across the vascular bed are gov
erned by a series of complex events including cytokine/chemokine produ
ction which in turn orchestrates the temporal expression of a cohort o
f adhesion molecules mediating the migration. Many of these adhesion m
olecules and their inducers are under the control of inflammatory resp
onse transcriptional factors such as NF kappa B and AP-1. Recently we
showed tepoxalin, previously known as a dual cyclooxygenase/lipoxygena
se (CO/LO) inhibitor, to be a potent inhibitor of NF kappa B-induced t
ranscription in vitro. In this study, we demonstrated that when admini
stered in vivo, tepoxalin but not naproxen (a nonsteroidal anti-inflam
matory drug, NSAID) or zileuton (an LO inhibitior), effectively inhibi
ts neutrophil migration into inflammatory sites in murine skin stimula
ted by either lipopolysaccharide (LPS) or tumor necrosis factor-alpha.
Immunohistochemical analysis indicates that 10-50 mg/kg of tepoxalin
inhibits neutrophil migration. It also effectively blocks the up-regul
ation of Mac-1 (CD11b/CD18) on neutrophils. Quantitative polymerase ch
ain reaction Mac-1 analysis shows that LPS-induced transcription of E-
selectin mRNA was dramatically suppressed by both 25 and 50 mg/kg of t
epoxalin, whereas the level of ICAM-1 was only affected by 50 mg/kg of
tepoxalin. Since it has been documented that the expression of E-sele
ctin and Mac-1 is regulated either directly or indirectly by the trans
cription factor NF kappa B, our studies provide in vivo evidence that
tepoxalin is a potent inhibitor of NF kappa B-mediated events in anima
l models and this novel molecular mechanism clearly defines it as a ne
w class of anti-inflammatory compounds.